Neurology® Podcast

Dr. Katie Krulisky talks with Dr. Kelsey Smith about the impact of menopause on women with epilepsy, including therapeutics and clinical management during midlife.
Read the related article in Neurology®Clinical Practice. 
Disclosures can be found at Neurology.org. 
Podcast Transcript: 
Dr. Jose Merino:
This is Jose Merino, Editor-in-Chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week.
Dr. Katie Krulisky:
Hello, and welcome to this episode of the Neurology Podcast. This is Katie Kruliski from the VA and University of Utah in Salt Lake City, Utah. Today, I have the pleasure of talking with Kelsey Smith. She's a neurologist and epileptologist at Mayo Clinic in Rochester, Minnesota. We will be discussing her recent paper published in the Neurology Clinical Practice Journal titled The Menopause Transition and Epilepsy: A Focus on Therapeutics. Welcome, Kelsey, and thank you for joining us.
Dr. Kelsey Smith:
Thank you so much for having me. I'm really excited to be here today to talk about this paper and this really important topic.
Dr. Katie Krulisky:
Yes. Your paper highlighted a staggering statistic, that women spend approximately 40% of their lives post-menopause. That shook me when I was reading this for a presentation on management of women in epilepsy. Being a woman, I felt totally blindsided by the statistic. I've never thought about it this way. I feel like so much of the emphasis of our clinical practice in epilepsy is choosing the right medications for pregnancy. And there is a lack of information and focus on women in perimenopause and post-menopause, even though a much larger percentage of the lifespan is spent in this phase. Let's go ahead and start with the clinical scenario. A 45-year-old woman with focal epilepsy is having some symptoms attributed to perimenopause and is interested in pursuing hormonal treatments. As her epileptologist, what is your approach to counseling her based on the current available data?
Dr. Kelsey Smith:
And when it comes to patients like this, it's a very important topic. And the first thing is that it really requires both an individualized and multidisciplinary approach. So I think first as an epileptologist, I want to understand all I can about her epilepsy, what the current seizure control is, what the current therapy is, what the epilepsy's been like over other life stages if she's had epilepsy no earlier, to understand how seizures may have been during menstrual cycles to know if there's kind of a hormonal driver of seizures that's been noticed through the lifespan. And then also I really want to understand about her menopause symptoms. What are the symptoms that are really bothering her that she's hoping to start the hormonal therapy for? And are those symptoms things like vasomotor symptoms or sleep disturbances? And are those actually also influencing her current seizure control? If the vasomotor symptoms are waking her up at night and she's not getting good rest, is this lowering the seizure threshold and actually driving worse seizure control?
Understanding all of this background's really important. And then to discuss with her what the data is about menopausal hormonal therapy and how it's related to epilepsy, how that data is really limited. And so we don't have a lot of data to go off of to provide counseling in this scenario. And all the studies that have really looked at this topic are really quite old, over 20 years old and have not used the same formulations of menopause hormonal therapy we use nowadays. And a lot of these studies didn't even use the anti-seizure medicines that we use nowadays. It's important to work with a patient like this and really let her know that despite the limited data, that epilepsy itself should not be a strict contraindication to considering menopausal hormonal therapy, but there are special considerations that we would need to think about, especially interactions between the hormones and anti-seizure medications and that she would probably require close following throughout using menopause hormonal therapy. I would also collaborate closely with a women's health expert so they can help us decide what the best hormonal therapy may be if it's indicated to treat her symptoms.
Dr. Katie Krulisky:
So a lot of these patients will ask, "When looking at hormones, I want to know where my hormonal levels are at now." Are you ordering their hormone levels?
Dr. Kelsey Smith:
Yeah, this is a common question that patients ask and I've also been working some with the women's health experts here at Mayo. And as we've worked on papers and things, it's not standard of care to draw these levels even throughout perimenopause and into menopause because of the fact that menopause is a clinical diagnosis. And also during perimenopause, there can be such wide fluctuations in hormonal levels. And so it's difficult to know what to make of different values and how that would influence clinical care. So overall, I'm typically not ordering hormonal levels, but would work with a women's health expert and if they though it would be helpful in a specific scenario, then definitely would consider it.
Dr. Katie Krulisky:
So on a very basic level, I've come to understand that in general, estrogen can make you more likely to have a seizure. Progesterone is protective. With that in mind, it sounds like you're not saying completely no to addition of estrogen in the hormone replacement therapy. Is that accurate?
Dr. Kelsey Smith:
Yeah, that is accurate. One of the things I learned by putting this paper together is that although some direct comparison of estrogen levels is difficult, but overall, usually actually estrogen that's used in menopausal hormonal therapy, the estrogen is less than the estrogen in oral contraceptive pills. And we don't see epilepsy as a contraindication to considering oral contraceptive pills, although obviously we need to take into consideration interactions with anti-seizure medications and things like that. But I don't think overall it should be a broad contraindication to considering the hormonal therapy. During perimenopause, the endogenous hormonal levels can fluctuate very significantly and there could potentially be an influence of seizure control based on those fluctuations. At least in theory, even menopausal hormonal therapy could potentially help with some of those fluctuations and could potentially be helpful, especially if some of the symptoms associated with menopause, like the sleep disturbances, like the vasomotor symptoms are actually making seizure control worse by reducing the seizure threshold.
Dr. Katie Krulisky:
That's a really good thing to keep in mind because there's a lot of fear-based decision-making surrounding women's health and seizure medications because a lot of that, we see a lot of that in pregnancy, right? We also see a lot of that in perimenopause and menopause. I think historically we've though, oh, estrogen is dangerous. You shouldn't have any exogenous estrogen. And then it seems like women are suffering the consequences from exactly like you've pointed out, very limited actual data. So just for review, what is the actual data that we're extrapolating this from?
Dr. Kelsey Smith:
Yeah. So there's a few older studies from the late 1990s and then early 2000s that are mostly observational studies asking women with epilepsy how did their seizures change with menopause hormonal therapy and things like that. And then there's one randomized controlled trial. It was published I believe around 2006, but it had very limited numbers, less than 25 patients. And that study said that with menopausal hormonal therapy, with the higher doses, there was a dose dependent relationship where seizures worsened with that therapy, the menopausal hormonal therapy. However, this study was using formulations that aren't typically in clinical practice anymore for menopausal symptoms as they're using more like estrogen patches and things like that. And so we really don't have data that looks at our currently used treatments in women's health and how it influences seizure control.
Dr. Katie Krulisky:
So I'll just say that the available data is extremely outdated and not even necessarily applicable to our current treatment standards in that area.
Dr. Kelsey Smith:
I would agree with that statement. I think we need more research, more data. And that was one of the motivations of putting this paper together, is just highlighting some of the gaps, but also using some of what we know from other life stages to highlight some of those interactions with anti-seizure meds, some of those things that we can at least talk to our patients about and we can try and improve clinical care.
Dr. Katie Krulisky:
And when you're selecting an anti-seizure medication for women, how heavily are you considering its association with osteoporosis?
Dr. Kelsey Smith:
Yeah, this was another very important topic when we're thinking about epilepsy and the menopause transition is osteoporosis. It's never too early to consider this and what anti-seizure medications are better for bone health because we know that there's many anti-seizure medications like enzyme inducing anti-seizure medications that can negatively impact bone health. And then there's even data that epilepsy itself can negatively impact bone health. So I don't think there's ever a time where it's too early to consider it and we should probably be considering it over the lifespan because if you get someone on an anti-seizure medicine that's really controlling their seizures, it's more difficult to switch them off to something else. But I do think that as people are reaching perimenopause age 40 or so, really reconsidering looking at that anti-seizure medication and how it could impact bone health.
And also just considering bone health in general is important for us epilepsy doctors. And so thinking about both recommending lifestyle modifications that are good for bones, but then also thinking about things like vitamin D calcium or when they should have screening. And really as they reach menopause and estrogen levels drop significantly, that's when we know that bone mineral density is really impacted and this is a time where we really need to be thinking about this and considering it.
Dr. Katie Krulisky:
The medication that always sneaks up on me is clobazam because I always think of it as a newer medication, but it can make you more likely to have osteoporosis, right?
Dr. Kelsey Smith:
Yeah. Some of the newer medicines, there's still less data out there, but most of the anti-seizure medicines or even some of the newer medicines suggest some newer data that they can negatively impact bone health. And then also interestingly, some newer studies that suggest even epilepsy itself, taking populations of patients with epilepsy that for different reasons may not be on anti-seizure medicines may have impacted bone health. And all these things are so important to consider when we have patients who are having seizures, who are at higher likelihood of having falls related to seizures, or as they're aging and they're on anti-seizure medicines that can make them dizzy and predisposed to falls as well.
Dr. Katie Krulisky:
That's so true. It's in addition to the epilepsy that can make you more likely to fall, all these other factors, the seizure medication, the sodium channel side effects, we have to keep in mind. When it comes to the screening tests, are you yourself ordering the DEXA scans or are you partnering with primary care? I've done it a little bit of both ways depending on the patient situation.
Dr. Kelsey Smith:
I've done it a few different ways. Sometimes it's easier if they have that close primary care and I'm going to rely on primary care to help me out if the DEXA is really abnormal anyway. So if I can, I'd probably collaborate with their primary care provider, but in some scenarios I have ordered the DEXA scans.
Dr. Katie Krulisky:
Because I know we both had these patients where it's like, if you don't order it, you know it's not going to happen.
Dr. Kelsey Smith:
Yeah. Yeah. And then, yeah, if I get the result and it's very abnormal, then I can work with other folks or even refer to endocrinology to consider treatment.
Dr. Katie Krulisky:
And we've touched on this a tiny bit, but overall, how do sex hormones impact seizure control?
Dr. Kelsey Smith:
Really simplifying a very complicated relationship we don't completely understand. So overall, it's felt that estrogen is to be pro-convulsive, can reduce the seizure threshold and make seizures more likely to occur. While progesterone, especially through its metabolite allopregnanolone, is more kind of anti-convulsant in nature. But like I said, it's simplifying something that we don't completely understand, but there's some basic science data that supports some of that.
Dr. Katie Krulisky:
When I do my presentation on this topic, I say exactly that, is that this is a gross oversimplification of the available information, but something that I always find interesting is that those GnRH cell populations themselves are vulnerable to injury from seizures themselves. So I wonder if that ties into the whole... Anyways, there's a lot more to learn. We can-
Dr. Kelsey Smith:
Yes, I totally agree with that statement. I think there's a lot more to learn.
Dr. Katie Krulisky:
So what's a practical approach to balancing the lamotrigine and estrogen interaction in midlife women?
Dr. Kelsey Smith:
It's just really something we need to anticipate the interaction as opposed to saying, "Oh, you're on lamotrigine, you can't be on anything with estrogen in it." And we need to be prepared for it. And so if menopause hormonal therapy is indicated and is being started, we need to know that baseline serum concentration of lamotrigine and need to recheck levels within two to four weeks of starting something with estrogen in it and adjust the dose as needed based on those serum concentration levels. So also if they've had epilepsy throughout their lifespan and have had changes in estrogen earlier in life, like during pregnancy, for example, or with oral contraceptives, we may have some idea by their history if they're more likely to have that drop in the lamotrigine level.
Dr. Katie Krulisky:
And when you're ordering lamotrigine levels, are you really going for a trough or are you more trying to get a consistent time of day? What's your approach with that?
Dr. Kelsey Smith:
Yeah, as much as possible, a trough. You need at least a consistent time of the day, but I do prefer trough levels, just because that's what a lot of the reference range is based on. And then if it's a true trough level, it will be a consistent time of the day.
Dr. Katie Krulisky:
What inspired you to put this review together?
Dr. Kelsey Smith:
This review was a lot of fun to put together and I really learned a lot about menopause and menopausal hormonal therapy. This was an effort though that was actually initiated through the Epilepsy from Childbearing Age to Menopause Consortium. This was from the menopause committee of this consortium, and so got to work with a lot of great co-authors on this paper to put it together, really learned a lot and really excited to see what this consortium can do over time to really advance care for women with epilepsy.
Dr. Katie Krulisky:
That is so cool. Can you say the name of this consortium again?
Dr. Kelsey Smith:
Yeah. So it's ECAM for short, and it's Epilepsy from Childbearing Age to Menopause Consortium. And it's only been around for a few years. I joined it a couple years ago, but it's really got a lot of wonderful people involved and different committees looking at care for women with epilepsy really across the lifespan.
Dr. Katie Krulisky:
I want to be a part of this group. That's so exciting.
Dr. Kelsey Smith:
Yeah, you should be. There's a website and everything. So yeah, if you Google it, you'll find it.
Dr. Katie Krulisky:
I feel like I have been somewhat radicalized by the process of having a child because all of just the things that women go through with the hormone fluctuation and truly the lack of available information on the impact of those hormone fluctuations is crazy. It is such a wild experience and to be in such a modern society and have so many blind spots within women's health is incredible in not a good way.
Dr. Kelsey Smith:
I totally agree with that statement and some of that sentiment as well, is that once I had children myself, then you really start looking at some of these things in different ways. And it's not something that us as epileptologists need to overlook or shy away from in clinic. Our patients a lot of times want to talk to us about these things, especially if they think it's influencing seizure control. And now trying to work on some research studies in the area and stuff, menopause is so hard to find in the chart. We're not always bringing it up. We're not addressing it. It's a topic that we really need to be thinking about because it definitely can impact our patients. And we do know some about the best ways to manage things over this life stage, especially based on some of the data we have from other life stages.
Dr. Katie Krulisky:
In general, what age range is menopause usually happening?
Dr. Kelsey Smith:
Yeah. So the average age of menopause in the United States is around 51 to 52. There's some earlier data from those other studies I already mentioned about menopause and epilepsy that suggests the age may even be younger for women with epilepsy, especially with uncontrolled seizures. We need to be thinking about this really between the ages of 40 to 55 or so.
Dr. Katie Krulisky:
So maybe even, considering I'm always asking women about childbearing potential, but maybe even including it in that discussion of are you still having a menstrual cycle?
Dr. Kelsey Smith:
Yeah, I think so. Are you still having a menstrual cycle? Is there association with your seizures? And if we get more comfortable with this topic, even understanding eventually menopause symptoms and how they could influence seizures. The other thing that's a little interesting in terms of epilepsy and menopause is vasomotor symptoms. People get these hot flashes. They just last a few minutes. They can happen any time of the day. And so I could even see how clinically it could be somewhat difficult for some patients to maybe differentiate from focal seizures and things. So it's just interesting in that scenario. They could not be clear, are those seizures, what are these new symptoms? So important for us as epileptologists to recognize.
Dr. Katie Krulisky:
It's important in epilepsy and I also think it's important, because I do some general neurology. I do general neurology and epilepsy as my practice, and I see it actually pervasively in neurology. I've had people come to me with symptoms of difficulty swallowing and just really broad symptoms. And then I remember one case specifically that they came back to me and said, "Oh, I was just going through menopause. I feel much better now."
Dr. Kelsey Smith:
Yeah. And the brain fog and other things that can come with menopause obviously can span different potential neurologic diagnoses.
Dr. Katie Krulisky:
Totally. And I have to say somewhat embarrassingly that I feel like I myself am not the most comfortable with discussing vasomotor symptoms associated with menopause. What topics are you screening for or what symptoms are you screening for?
Dr. Kelsey Smith:
When you see someone in this midlife stage just asking, "Are you still having menstrual cycles? Do you feel like you've gone through menopause?" Because it's difficult to get that information or impossible to get that information without just asking about it. And then just asking if they're having symptoms they think that have changed with fluctuations in menstrual cycles as well to suggest they're in perimenopause and if they're having vasomotor symptoms or new sleep disturbances, what those could be like.
Dr. Katie Krulisky:
I know the sleep thing comes up a lot with our patients. Do you have a first step of approaching that with the sleep issues or are you referring, trying to manage it yourself?
Dr. Kelsey Smith:
I try and understand what the sleep disturbance is. Is it falling asleep? Is it frequently waking up? If there's any chance there could be potential sleep apnea playing a role, then I usually do an overnight oximetry and consider referral to look for that because sleep disturbance from sleep apnea, which can obviously start at any age, but mostly in older adults, if they're having problems with sleep apnea, then that needs to be managed first.
Dr. Katie Krulisky:
Thank you so much, Kelsey, for taking the time to discuss your review on management of epilepsy in midlife women. The paper is titled The Menopause Transition in Epilepsy: A Focus on Therapeutics, and you can read all the details in the Neurology Clinical Practice Journal.
Dr. Stacey Clardy:
This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org/podcast for our full list of past episodes, or you can also search by keyword in your podcast app for any neurology specific topics.

Dr. Margarita Fedorova talks with Dr. Pascal Geldsetzer about how the herpes zoster vaccination may have neuroprotective effects, potentially delaying or preventing dementia. 
Read the related article in The Lancet Neurology.
Disclosures can be found at Neurology.org. 
Podcast Transcript: 
Dr. José Merino:
This is José Merino, editor-in-chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week.
Dr. Margarita Fedorova:
Hi, this is Margarita Fedorova and I'm a neurology resident at the Cleveland Clinic. Today, we're exploring a study that speaks to an idea that's been building for a few years now, that vaccination itself might be neuroprotective.
I'm here with Pascal Geldsetzer, a physician and epidemiologist at Stanford University. Pascal is the author on a paper published in the February 2026 issue of Lancet Neurology titled "Herpes Zoster Vaccination and Incident Dementia in Canada: An Analysis of Natural Experiments." What makes the study different is how they got at the question. When Ontario started publicly funding the shingles vaccine, eligibility came down almost entirely to date of birth. People born a few weeks on one side of a cutoff could get the vaccine for free, and people born a few weeks on the other side could not.
That left Pascal and his colleagues with two groups of older adults who should be alike in essentially every way, except their access to the vaccine. And they asked whether those groups went on to develop dementia in different rates. We wanted to bring Pascal to the podcast because this is a question our patients are already asking us in clinic, and because vaccination is one of the few things we can offer an older adult that might actually protect the brain. Pascal, welcome to the podcast.
Dr. Pascal Geldsetzer:
Thank you very much for having me.
Dr. Margarita Fedorova:
Let's start with a take-home message. If I'm rounding with a team tomorrow and I get to teach them one thing from your paper, one thing I want them to still remember six months from now, what should that be?
Dr. Pascal Geldsetzer:
I think it is that for shingles vaccination and dementia, we now have a body of evidence from observational data that we're usually never able to obtain in terms of the fact that we are able to get at cause and effect in a much more plausible way than we are usually able to. And we can say here now that shingles vaccination may well have a delaying or preventing effect on the dementia disease process.
Dr. Margarita Fedorova:
Before we get into your study, give us the background. We tend to think about dementia in terms of amyloid, tau, vascular risk, and lifestyle. Where do vaccines come into it? And is this really a shingles story or is it something broader about vaccination and brain health in older adults?
Dr. Pascal Geldsetzer:
Yeah, so unfortunately we don't know exactly. And so of course, broadly speaking, it could be either through reducing reactivations of the chickenpox virus or varicella zoster virus, which we know is a neurotropic virus, which we know reactivates throughout life. And so reducing these reactivations and probably accompanying neuroinflammatory processes may well have benefits. But there may also be a broader potentially virus-independent immune mechanism at play here that may also apply to other vaccines than just shingles vaccination. So we don't really understand the mechanism yet. It's a very interesting and fascinating area of research and hopefully we'll learn more in the future.
Dr. Margarita Fedorova:
We already knew from a lot of prior work that shingles vaccine was associated with a lower risk of dementia, but in the paper you were direct that those earlier studies can't really speak to cause and effect, and that's a really big part of why this one matters. What goes wrong when we simply compare vaccinated people to unvaccinated people and how does your design get around it?
Dr. Pascal Geldsetzer:
So this gets to the fundamental problem that we usually have in observational data analysis in epidemiology, right? It's that those who get a certain intervention, who get a certain medication or who decide to adopt a certain lifestyle regimen, certain diet, or who decide to get vaccinated are just very different to those who don't. And especially in the case of vaccination, we know there's this healthy vaccinee bias whereby those who have better preventive health behavior, health motivations, et cetera, are the ones who go get vaccinated and they have a lower risk of dementia in any case regardless of vaccination. And we can try to adjust for these differences between these groups. And that's what we do in epidemiology with all sorts of fancy methods. But at the end of the day, what we're restricted to is the information that we have in the data sources that we're analyzing.
And I just don't have very much information at all in electronic health record data, medical claims data, et cetera, on all these various health behaviors, health motivations, dietary behaviors, et cetera, et cetera. So it becomes really hard to know whether we are really truly able to adjust for all of these differences. What we are doing instead in these shingles vaccination natural experiment analyses is we're changing the comparison group to something that's much more close to what we have in a clinical trial. And of course the clinical trial is what we need to ensure that the comparison groups are comparable because we know all that's different about them is whether a coin landed on heads or tails. And here in our natural experiments, we know that all that's different about the groups that we're comparing is whether they happen to be born essentially by random chance a few days earlier or a few days later because our natural experiments are exploiting these date-of-birth-based eligibility rules for shingles vaccination.
For instance, in Wales, in our first paper that we published in this series, we know that those who had their 80th birthday just prior to the start date of the shingles vaccination program, which just so happened to be September 1st, 2013, were ineligible and remained ineligible for life. Well, if you had your 80th birthday just after, you were eligible and we see a jump in your probability of ever getting the vaccine by just a week's difference in birth from 0% to 50%. So we have now this really sharp contrast just by the fact that you were born a few days earlier or a few days later. And that's what makes our comparison groups different and the effects that we're seeing much more likely to reflect true cause and effect rather than just a correlation.
Dr. Margarita Fedorova:
And for this current natural experiment, what exactly did you find? Without talking too much about the numbers, can you tell us whether we think we're preventing dementia or delaying it with the vaccination?
Dr. Pascal Geldsetzer:
We don't know exactly if we are preventing or delaying dementia. That's an active research area in my group to truly understand this. But what we're seeing is that these groups of people were born just on either side of this eligibility cutoff. Those who happen to be eligible because they were born just a little bit later have a lower probability of receiving a new dementia diagnosis in the future. It's hard to pinpoint the exact magnitude of the effect because our method really zooms in on people born just around this cutoff. And of course also various data limitations that we usually run into such as having knowledge on your exact vaccination uptake levels in these two groups dementia and ascertainment, et cetera. But what we can say is that there seems to be a large, certainly clinically meaningful protective effect for dementia in the future.
We always have to bear in mind the intervention here is a simple one-off inexpensive safe intervention that's already recommended in any case for shingles prevention. So the bar that this intervention has to pass in terms of showing efficacy is much lower because the downsides are so low. This is a really exciting, for me at least, it's a really exciting area of research.
Dr. Margarita Fedorova:
I wanted to circle back to you talking about randomized trials. So is a trial potentially the right next step here and what would one have to look like to settle this question?
Dr. Pascal Geldsetzer:
Yes. So that is the dream that I'm currently pursuing, trying to see if we can get the funding together for a clinical trial of the shingles vaccine that we have been studying in all our natural experiments, which is an off-patent shingles vaccine. It's the old live attenuated vaccine and may well be specific the effects that we're seeing to that vaccine. So just to reduce uncertainty using that vaccine is important. But that also means for funding, we really have to try to see if we can get philanthropic funding, private foundations. So yeah, that's what we're hoping for somehow. But yes, really to conclusively test this question, this link, what we need at the end of the day is a clinical trial and also to convince the medical and public health community. And also because it offers just really important opportunities to learn more about this link that we can't in observational data analysis.
So it's a trial that would be ambitious in terms of its sample size because we do need here, we have the evidence for dementia prevention and that means we need a large sample size to be able to have enough events. However, we already start seeing survival curves for dementia incidence separating after about a year and a half or so, a year and three months. So a four-year follow-up period, for instance, would be reasonable. And so it's not a trial that would need to take decades. And yes, that's what I'm pursuing at the moment.
Dr. Margarita Fedorova:
I do want to briefly talk about any important caveats that we have in this project. I'm thinking in particular about the sex difference since the effect looked stronger in women, and I suspect that this is one piece that people will latch onto. How much weight should we be putting on that?
Dr. Pascal Geldsetzer:
Yeah, it's something that we tend to be seeing in our data sets that there are stronger effects, stronger protective effects among women than among men, but it doesn't mean that men do not benefit. And there's also still some uncertainty as to really how large or important this difference is between the sexes. It was particularly marked in our first analysis, but that was a bit of an outlier in terms of that relationship.
Dr. Margarita Fedorova:
I also wanted to talk about what to do with this in terms of clinical practice and specifically patient counseling. Most of us in neurology don't think of ourselves as the people responsible for patients' vaccination. Should we be? And is there a case for a neurologist asking an older patient or patient with cognitive complaints whether they're up to date on their shingles vaccine?
Dr. Pascal Geldsetzer:
It is a recommended vaccine for adults 50 years and older in the US. We know it prevents shingles. We know shingles can have a variety of complications. There's also some evidence that shingles vaccination potentially has benefits for cardiovascular and cerebrovascular disease risk reduction. So putting all of this together, I know clinicians are busy and that is probably the downside, having the bandwidth and taking the time to do this, but I certainly think it can't hurt to check on vaccination status, to recommend vaccination in those who are eligible for the vaccine. And for dementia, we can say now that there may well be benefits also for dementia, for cognitive health in older age.
Dr. Margarita Fedorova:
And in terms of the underlying mechanism of the vaccine, there was a paper last year on the AS01 adjuvant that raised the possibility that the benefit isn't entirely about the virus, but more about what the vaccine does to an aging immune system. If that turns out to be right, it would say something much bigger about vaccination in older adults. Where does your instinct land?
Dr. Pascal Geldsetzer:
It's hard to say. I'm probably the wrong researcher to ask about this because I don't look at basic science so much. I'm really more of a data cruncher, but certainly it's a possibility. We know these broader immune mechanisms are important for vaccines and seem to vary by particular types of vaccines. We just don't know yet to what degree they impact on chronic diseases, these broader mechanisms, including dementia. There's a strong case to be made as well, of course, for something specific to the varicella zoster virus, given that we know these neurotropic herpes viruses are in this constant interplay with the immune system, cause these neuroinflammatory processes, and that this poses some sort of chronic immune stress that drives inflammation in the body is something that, and that could be particularly important in older age as the immune system weakens. It's certainly something that seems to me at least very plausible as well from a biological perspective.
Dr. Margarita Fedorova:
So let's say I have a 72-year-old in clinic next week. She's read a headline about the shingles vaccine and dementia, or maybe she's hesitant about vaccines in general. What is a fair and honest thing for me to tell her? How would you use this evidence in that conversation without overselling it?
Dr. Pascal Geldsetzer:
Yeah, so of course I'm a researcher. I try to shy away from making vaccination recommendations, but practically speaking, I would certainly say it's safe to say that the shingles vaccine is a recommended vaccine for older adults. We know it prevents shingles and its complications. And we now have an additional body of evidence that suggests that the vaccine may also have benefits for dementia for cognitive health in older age. That is a very fair thing to say.
Dr. Margarita Fedorova:
Thank you so much. I've been speaking with Pascal Geldsetzer from Stanford University, who's a senior author on a paper published in the February 2026 issue of Lancet Neurology titled "Herpes Zoster Vaccination and Incident Dementia in Canada: An Analysis of Natural Experiments." Thank you for your time and insight today.
Dr. Pascal Geldsetzer:
Thank you. Thank you so much for having me.
Dr. Stacey Clardy:
This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org/podcast for a full list of past episodes, or you can also search by keyword in your podcast app for any neurology-specific topics you want to learn about.

Dr. Jason Crowell talks with Dr. John McDonough about the historical and economic factors shaping the US healthcare system and why understanding these systemic forces matters for neurologists and patient care. 
Read the related article in The Harvard Gazette. 
Disclosures can be found at Neurology.org. 
Podcast Transcript: 
Dr. Jose Merino:
This is Jose Merino, Editor-in-Chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week.
Dr. Jason Crowell:
Hey, this is Jason Crowell from Norton Neuroscience Institute in Louisville, Kentucky. Thanks for listening to today's Neurology Podcast. Most of our audience members are practicing neurologists, you're in training or you're in an academic setting or in private practice. And for those of us who are in practice, we are well aware of the challenges of helping our patients access drugs, getting prior authorizations approved, the other areas of friction that exist in our healthcare system. And I would say that whether we realize it or not, these areas of friction are symptoms of larger choices about how our hospitals and clinics operate.
And so to help us think about these things, today we've invited John McDonough to join us. John is a professor of public health practice at the Harvard T.H. Chan School of Public Health. We recently read an article about John's work published August 18th, 2026 in the Harvard Gazette and wanted to invite him to join us today.
So John, thank you so much for your time.
Dr. John McDonough:
Pleasure to be here with you, Jason. Thanks for inviting me.
Dr. Jason Crowell:
So John, in this piece that I read in the Harvard Gazette that was describing some of the work you've done, you point to a specific historical pivot around 1980 when US healthcare spending grew at a pace that's disconnected from the rest of the industrialized world. And that was 40 to 50 years ago, so most of our audience does not have experience with the practice of medicine prior to that time. The title of your upcoming book is America's Wrong Turn: US Healthcare in the Neoliberal Era. Can you help summarize what you mean by this wrong turn that happened? And also, can you just give us some background about what you mean by this neoliberal era?
Dr. John McDonough:
So I've been influenced by a Yale political scientist, Stephen Skowronek, who suggests that there's a helpful way to look at American political economic history, not through the lens of individual presidential terms like say the Nixon era or the Reagan era or the Obama era, but to look at larger multi-decade politico economic eras where there are dominant political strains. And Skowronek says we've had five of these eras over the 250 years.
But just to talk about the two most modern ones that are most relevant to our discussion here. The first one started in 1933 with Franklin Delano Roosevelt's inauguration as president in the midst of the Great Depression. And inaugurating an era that became known as the New Deal era, which was an era of muscular federal and state governmental leadership and guidance in terms of steering the economy toward greater productivity, toward higher wages, toward all different kinds of innovations like social security and Medicare and Medicaid.
That era didn't end when FDR died. It went on until 1980 when it collapsed in the end of the Jimmy Carter presidency with upset and anger over what was then called stagflation, the Iran hostage crisis, the gas crisis from the Middle East with OPEC. So it was succeeded in 1980 with the inauguration of Ronald Reagan. And Ronald Reagan came in openly talking about let's move away from the New Deal era. It's not working anymore. We have to go forward. And that era was in some ways, people call it the neoliberal era because it was an era defined by a set of economists like Milton Friedman, Friedrich Hayek, other folks, Robert Bork, James Buchanan and others.
And it represented a move toward let's have a much more muscular free market defining all manner of sectors of American economy and American society. Let's de-emphasize government to the maximum extent possible and just allow the free market to run. We have a professor at Harvard in the college, Naomi Oreskes, who refers to the era as the free market fundamentalist era. That's her label. I prefer neoliberal just because neoliberalism was actually a global movement in the '70s, '80s and beyond. It still lives on today in many places and in many ways.
And it was not aimed at trying to transform American medical care or our healthcare system, but healthcare and medical care in the US is so huge and so important that it's really impossible to imagine that we would go through this societal revolution and medical care would go untouched. So my premise is that it did get touched quite a bit in a series of ways that I look at and say it created a lot more harm than benefit. And so inviting people to look at the neoliberal phenomenon in terms of its impact on health and medicine in the United States.
Dr. Jason Crowell:
One of the key shifts that you highlight is the massive market consolidation that has occurred here in the healthcare system. And we've seen this in our own neurology practices. Small independent subspecialty practices are very rare these days. Many of them have been bought up by health systems or private equity firms. And we understand that when healthcare merges occur, the claimed value is in regards to more efficiency, less overhead, but you cite research that shows prices actually increase following hospital mergers. So has this consolidation in healthcare, how has it affected the delivery of healthcare?
Dr. John McDonough:
So antitrust, anti-monopoly, anti-oligopoly began in earnest in the United States in the 1890s after the passage of the Sherman Antitrust Act. And over the succeeding 90 years, we had a belief that big corporate concentration in any sector, whether it's a humongous sector like steel or railroads or even relatively minor sectors that mattered in the economy, had to be confronted and addressed when you had companies that were growing by consolidating, swallowing up hostile takeovers that created then market dominance for one or several firms.
And in the 1970s, and this came straight out of the neoliberal era, it was led by a man by the name of Robert Bork, who many people have probably heard of, former Solicitor General under President Richard Nixon, failed candidate for the Supreme Court in the mid-1980s. But in the 1970s, he took on the antitrust consensus that had governed the nation for 80 to 90 years. And he said, "We've got it all wrong. Big is not bad. If companies get big, it's because they deserve to be big and we should just let that happen. And if they get beaten up by the market, that'll take care of it, the discipline of the market."
And he put these ideas together into a book and the book was called in 1978, The Antitrust Paradox. And he proposed what he called the consumer welfare theory of antitrust, which says that if two companies want to come together and they can demonstrate that consumers will benefit from lower prices, then it should be a green light. Do what you want, go ahead. And in the early 1980s, they rewrote fundamentally the federal antitrust guidelines, which provide the consensus to federal judges, federal prosecutors, states, everybody. Here's how we see it. And they rewrote them in 1981 and '82 to bring the consumer welfare hypothesis of Robert Bork into the mainstream in terms of this is how we look at antitrust.
And so we had about 40 years of diminished antitrust enforcement kind of going into hibernation that affected the medical and healthcare community. So by the year 2020, in US counties, about 95% of US counties had what's called highest levels of corporate concentration. And with medical specialization at that point, it was about 65%. It's more now. For insurance companies, it was 75% highly concentrated markets all over the country. And there's a lot of newer economic research over the past several years that says that if we really want to understand why medical care, healthcare prices, insurance premiums, everything else is going up so much, they're looking at it. They're saying the extraordinary degree of corporate concentration over these decades has to be considered one of the prime, if not the most important culprit in terms of explaining what went on and how we got so consolidated relative to today versus where we were in the late 1970s.
Dr. Jason Crowell:
Let's turn to drug costs for a second. We have talked about drug costs on this podcast for several years. We have closely followed the work of ICER, the Institute for Clinical and Economic Review, and the work that they've done in helping us understand the value of drugs. Our multiple sclerosis colleagues are very familiar with the high cost of drugs. We now have these anti-amyloid therapies available for patients with certain neurodegenerative disorders that our cognitive neurologists are using.
And of course we celebrate these new drugs for our patients with neurological diseases, but the price tags that come with some of these drugs can be staggering and are often associated with significant friction in terms of accessing them. So whether it's step therapy or prior authorizations or large out-of-pocket copays. Would you say that these administrative frictions are a deficiency of our current system, or a necessary feature to contain the cost?
Dr. John McDonough:
They are to some extent signs of dysfunction in the system in the sense that they've led to outcomes that have significantly diminished the level of competition and competitiveness. Just one data point for you, between 1985 and 2002, the market share of the top 10 firms in the pharmaceutical industry more than doubled from 20% in 1985 to 48% in 2002 in global sales, and it's gone up even more today. So we've seen the same story of heavy corporate consolidation. We see that far more than the money that pharmaceutical companies spend on research and development, which is the claim of what they need all this money, is substantially greater amounts of money sent out to their shareholders in terms of dividends and financing stock buybacks to an extraordinary extent that we've never seen before.
Stock buybacks are when a company basically just buys back shares from stock owners just to shrink the share so that everybody's price then rises. Prior to the 1980s, since the 1930s, the New Deal era, buybacks were illegal. They were outlawed. They were considered to be corporate exploitation and manipulation that should not be permitted. And now it is just a regular feature that is part of another related growing phenomenon that we've seen over these past 40 to 50 years, which is the term financialization. That across the medical care sector, more and more of what is done is not being done with the prime purpose of creating products, improving care, improving people's health.
It's being done to increase the financial wealth of the holders of capital to an extent that we have never really seen since way early in the 20th century, a long time ago. And so we see it in pharmaceuticals, we see it in medical devices, we see it across the board, we see it in hospitals. We even see it to a significant extent in the nonprofit hospital sector where we have had the creation of what we call mega providers who are now no longer just care delivery organizations, but they are major research institutes.
And that has advantages and that has a role, but it is like everything else there's sometimes something called too much of a good thing. Or too much of the magic of the market in a way that then has harmful side effects and harmful results in terms of what people most want. We've had 40 years of tremendous growth in the size of our healthcare system in the United States as we have seen life expectancy still continue to grow, but grow way, way behind all of the other leading advanced industrial nations. And if we're not here about improving life expectancy, what are we here for?
Dr. Jason Crowell:
To quote you, you said it's going to take radical action, quote, "Radical action to make changes that fix the system." So I would ask if you were advising healthcare policymakers today, what's the top two or three things, the top interventions that you would provide to improve the lives of our patients? Or by proxy to help us as neurologists and physicians who are trying to help these patients?
Dr. John McDonough:
I would say right now that we are in an incredibly vital and dynamic period right now in 2026. In some ways it reminds me of 2005 and '06 when people were thinking about the next wave of health reform in the United States, which ended up resulting in the Affordable Care Act. But the people were looking three and four and five years ahead and starting to ask the questions, what's most important? What would have the greatest impact? I see us in a similar phase right now, and so there are loads of individual ideas. I put them into categories.
We really need to re-empower patients and consumers in this system who have been turned into widgets for the financialization of the whole sector. We need a brand new patient bill of rights in the United States that gives patients protections around prior approvals, around excessive cost sharing, around various forms of manipulation by the market. Signing non-disclosure agreements and mandatory arbitration, rather than being able to take grievances to court, for example, that is now almost universal.
We need a new set of protections for physicians, nurses, and other parts of the healthcare workforce to be able to exercise their rights and protect their professional values and identities in the face of a corporate takeover of so many parts of American medicine. We're dealing so much with moral injury to providers who find themselves at the wrong end of the stick of private equity, for example, and other kinds of corporate irresponsibility.
We need a new code of conduct for corporations. We need a much more aggressive attitude toward market consolidation, whether it's monopoly or oligopoly or whatever. And we saw that, we started to see that in the first four years of this decade when President Biden put in a woman named Lina Khan in charge of the Federal Trade Commission and Jonathan Cantor in charge of the Justice Department's anti-monopoly division.
We saw over those four years, and it was too brief a time to take full hold, but an extraordinary turning of the tide in terms of the ability of the large companies to take over at will anything that they wanted and to be able to merge and consolidate in ways that has been harmful, particularly looking at the vertical integration of major companies such as, for example, United Health Group or CVS. We've seen no longer just growing in their own spaces, but so United Health taking over providers, taking over pharmacy benefit management, taking over health data in ways that are just, it's too much power in one entity.
And it has the tail wagging the dog and probably at this point, the tail is larger than the dog itself in many ways. Lots of categories also. We need to really rethink access to care in the United States, how people obtain it. And so a lot of not just individual interventions, we're going to need whole categories. We didn't get to this place through one or two or three or four policy changes. We saw 40 years of policy changes inside and adjacent to the medical care sector, and that needs to be addressed, but it's not going to happen overnight.
It's a long-term project. And it's not about moving backwards to where we used to be 50 years ago. It's about a new vision of where we have to move forward in this age, in this era right now.
Dr. Jason Crowell:
And John, as we wrap up here, I started by saying most of our audience members are busy in clinical care, maybe some do research, but we see a lot of patients, inpatient hospital duties. It can be easy to hear about these massive, very large scale policy issues and feel ill-equipped to make any difference. And so for the neurologist who's listening to this podcast on her commute home, who wants to provide great care, but she feels overwhelmed by the surrounding systems of care, do you have any recommendations about what she and all of us can be doing to meaningfully engage with or push back against some of these issues we face?
Dr. John McDonough:
I know people in your specialization, Jason, are incredibly challenged keeping up with the fast pace of innovation in terms of research and innovation and discovery, and find it hard to keep up with that in many ways because of how fast things are moving in this new environment. I would suggest that it's also important to pay attention to the political and economic factors that surround your specialization. To understand and think about how changes going on in these areas that are adjacent to medical care practice and to surgical practice today are having real impacts in terms of how people are able to deliver care in ways that they think is most effective and efficient for their patients.
And so I'd say that paying attention to some of these economic and political factors, weighing in with members of Congress who are considering perhaps changes to the rules around monopoly and consolidation or private equity, or other manifestations of the financialization and corporatization of American medical care, it's very important to do some education. For example, if you want to understand where we are or where we've come from in terms of market concentration and monopoly, I just recommend a single book called Goliath by a guy named Matt Stoller, S-T-O-L-L-E-R. Which is a 140 year history of monopoly and antitrust in American society. A different explanation, one that I find quite compelling and quite important.
Dr. Jason Crowell:
Terrific. We really appreciate you joining us today, John. Again, I've been speaking with John McDonough. He's a professor of public health practice at the Harvard T.H. Chan School of Public Health. We came across his work that was described in the Harvard Gazette published back on August the 18th. John, thank you again for your time and your expertise. We really appreciate it.
Dr. Stacey Clardy:
This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org/podcast for our full list of past episodes, or you can also search by keyword on your podcast app for any neurology specific topics you want to learn about.

Dr. Shuvro Roy talks with Dr. Daniel Daneshvar about the prevalence of CTE at death among NFL players and the association between CTE severity and the risk of dementia. 
Read the related article in the BMJ. 
Disclosures can be found at Neurology.org. 
Podcast Transcript: 
Dr. Jose Merino:
This is Jose Merino, Editor-in-Chief of the Neurology family of journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening, and have a great week.
Dr. Shuvro Roy:
Hi, this is Shuvro Roy from the University of Washington, and welcome to today's Neurology Podcast. We'll be covering a study titled Prevalence of Chronic Traumatic Encephalopathy and Death in National Football League Players: A Retrospective Population-Based Cohort Study from 2008 to 2001, published in BMJ. We're joined by lead author Daniel Daneshvar, Chair of Spaulding Rehabilitation at Harvard Medical School. Dan, thanks for joining us.
Dr. Daniel Daneshvar:
Great to be here. Thanks for having me.
Dr. Shuvro Roy:
So Dan, this study has already received widespread national attention, but please give us the headline. What did you find and what's the number one thing that you want listeners to remember?
Dr. Daniel Daneshvar:
So this was a study looking at how commonly this specific neurodegenerative disease called chronic traumatic encephalopathy or CTE, how commonly this occurs in a cohort with a lot of repeated traumatic brain injury exposure, namely former National Football League professional football players. And what we found was that between the years of 2016 and 2021, so for that five-year period, the absolute minimum prevalence of CTE at death in this group was 25%. The absolute maximum was 98%, and the true rate is somewhere in that range. Now, for context, in the general population in community cohort studies, the prevalence of this pathology is somewhere south of 1%.
Dr. Shuvro Roy:
And what does this study add to our current understanding of CTE and neurologic disease associated with head trauma?
Dr. Daniel Daneshvar:
So we've long known that individuals who have experienced repeated traumatic brain injury exposure, whether through sports like NFL, NHL players, professional soccer players, whether through occupational exposures like in the military or as in individuals who experience intimate partner violence, we've long known that these individuals have higher rates of neurodegenerative disease. But what we haven't known is just how much higher that rate is. And what this study has shown us is first off that this is alarmingly high in former professional football players at death. And then the second thing that this study shows us is that this pathology is unsurprisingly very linked to clinical symptoms, including with more severe disease, cognitive impairment that's so severe it results in dementia, meaning impairment in someone's ability to perform activities of daily living, including feeding, bathing, dressing, grooming, toileting, those kinds of things.
Dr. Shuvro Roy:
As you pointed out, your primary finding was that there was this maximum versus minimum prevalence, which ranged from anywhere from 98% to 25%, so obviously a wide range. But to help us understand this study, can you walk us through that methodology, the minimum and maximum prevalence approach? Why a range rather than a single estimate? And you mentioned that the number is likely somewhere in between. Where do you think that true number sits, if we even can estimate?
Dr. Daniel Daneshvar:
So to understand why there's a range, it's helpful to understand how we got to these numbers. And so when we looked at the individuals who had CTE who played in the NFL across three brain banks, mostly the BU CTE Center, but also the Mount Sinai Brain Bank and the UCSF Alzheimer's Disease Center Brain Bank, when we combined all NFL players across these brain banks, we found that NFL players had a 93% prevalence of CTE at death, but that 93% represents a selected cohort. These individuals who chose to donate their brains more often than not chose to donate because they or a loved one had some concerns about them, not always, but many times. And so we don't believe that the true prevalence in NFL players is 93%, but what we wanted to get at is what could that true prevalence look like? And so we took advantage of the fact that amongst the NFL community, brain donation is something that has been less stigmatized over the past couple decades and is something that is very common.
And so we said for the lowest, the conservative minimum prevalence of CTE, let's say that everybody who was not studied by one of our brain banks, that every single professional footballer who died during that time period had no CTE at all in their brain. If we make that assumption, then the absolute minimum over those last six years of the study is that 25%. Now, it's important to note what that assumption entails. That assumption assumes that, for example, the people who were diagnosed with CTE at other brain banks that were not included in this study, it assumes that they did not have CTE, even though they were diagnosed with CTE at other brain banks. That conservative minimum assumes that the 16% of people with dementia so severe, it was listed as the actual cause of death on their death certificates, the 16% who didn't donate, that they did not have CTE either.
Now, of the people who did donate, for the folks who had dementia, 96% of them had CTE. So that's quite an assumption. We're assuming that they were all clean too. Despite those assumptions, the conservative minimum of CTE prevalence amongst these NFL players is one in four. Now, the maximum on the other side assumes that the only individuals who played in the NFL who died during that time period that didn't have CTE were the ones that we laid eyes on, and so that everybody else, they did have CTE. That's how we get the upper bound. And so when I say that range is somewhere in the middle, based on those assumptions, it's almost certainly higher than that 25% and likely substantially higher.
Dr. Shuvro Roy:
So essentially trying to maybe correct for the possibility that maybe there's a "sick bias" or selection bias of the brains that were donated, but even the 25% is almost certainly too conservative, considering it is likely that those folks with dementia, at least some of them had some degree of CTE. To that point, beyond prevalence, you showed that stage four CTE was strongly tied to dementia with 90 plus percent of those donors affected. What does that add to the argument about CTE pathology mattering clinically? Can you speak a little bit more to that?
Dr. Daniel Daneshvar:
It's pretty clear at this point that CTE pathology is associated with a substantial cognitive impairment, especially as it gets severe. In a different study, we took a look at individuals who had CTE in the absence of any other neurodegenerative disease, and we found in that study that individuals with more severe pathology were more likely to have dementia and specifically with stage three and stage four CTE. In this study, similarly, we also found that in individuals with CTE in the absence of other neurodegenerative pathology, which represented 53% of donors who had CTE that had no other neurodegenerative disease had dementia too.
So CTE clearly can result in dementia when the pathology is severe. But that's, again, not surprising for anybody in the neurodegenerative disease space because the pathologic marker that's most closely linked to cognitive impairment in a disease like Alzheimer's disease, it's not the amyloid pathology, it's the tauopathy, it's the phosphorylated tau, the same neurofibrillary tangle pathology that we see in Alzheimer's. When that disease occurs in a different pattern, but also in CTE, it's not surprising that we see individuals with cognitive impairment.
Dr. Shuvro Roy:
You also looked at the death certificates of the donors in these cases, and death certificates missed roughly 70% of the dementia that your clinicians identified. I think about CTE in the news and how many prior players who have since been found to have CTE posthumously were not necessarily identified to have dementia at the time. What does this finding mean for some of the earlier NFL mortality studies that relied on these numbers of the percentage of players who had dementia?
Dr. Daniel Daneshvar:
Again, it's not particularly surprising for anybody in the neurodegenerative disease space that death certificates under-report the prevalence of dementia, because many individuals die with dementia but may die of say an MI or something else. But we've both been the beleaguered intern in the ICU in the middle of the night that has unfortunately had to write a death certificate for a patient of ours. And oftentimes what we're writing is the most proximal cause of death. So we might write that sepsis or pneumonia was the cause of death, but might not include on the death certificate that the sepsis was due to urosepsis related to dysphagia related to dementia. Those factors aren't typically what we are including in the death certificates. And so we know that death certificates are under-counting the rate of neurodegenerative disease. But what this study allowed us to do was put a number to it to let us know that we're missing the vast majority of individuals who are dying with dementia but of other processes if we only look at the death certificates.
And so when we look at death certificates and we try to ascertain the causes of death for individuals, we might erroneously think that something like a heart attack is a bigger issue for NFL players than something like dementia, but that's why it's so important to take a look at what the population averages are. And so when we look at something like MI for NFL players, they die with MI, as we showed in a paper we published in Lani City Clinical Medicine last month. They die at a lower rate than the general population of MI, unlike dementia where neurodegenerative disease causes of death occur at a substantially over four times higher rate than the general population.
Dr. Shuvro Roy:
Understood. Dan, I want to change tracks slightly. There's some really interesting findings in these studies that build off of prior work, as you mentioned. In this study, for example, career length predicted how severe CTE was, but not whether it was actually present. Back a few years ago, we had the opportunity to interview Anne McKee, one of your co-authors on this study on the same topic. And one of the major takeaways, at least at that time, was that duration of career did predict CTE presence in those studies. How should we think about these newer data in that context of those prior studies?
Dr. Daniel Daneshvar:
Yeah, so great question. In this study, 93% of the decedents who donated had CTE pathology. And so we're looking at a profound ceiling effect rather than our previous work, which has looked at individuals across the entire range of exposure. To put it differently, what we effectively found in this study is that if you had 90 plus pack-years of smoking, that smoking 90 versus 95 pack-years didn't really play as big a role in whether or not you got lung cancer. It played a bigger role in how severe that lung cancer was for the people who got it. But there are some people who for genetic or other reasons, they just didn't get the disease. That's what we found effectively in these analyses. When you restrict it to the most extreme outliers in exposure, the people who had the most exposure to repeated traumatic brain injuries, the relatively small differences between that extreme end, it didn't predict CTE status, but it did predict the severity of the pathology.
So if you had 16 years of American football versus 18 years of American football, that extra 10,000 Gs or so of head impact exposure, that didn't predict CTE status. But for those who unfortunately did have CTE pathology, it very strongly linked to how severe that pathology was.
Dr. Shuvro Roy:
Understood. That makes a lot of sense. So essentially, that signal may still exist. It's more just with this particular population, given the sheer prevalence of CTE, we likely would not have the granularity to dig out the presence or lack thereof of CTE and how much that played into it, really just the severity. So that makes sense.
Dr. Daniel Daneshvar:
It's also just important to note that the majority of the people that were included in this cohort, they were part of the previous studies that included the full range of donors. For example, there were 338 people in this study that donated that played in the NFL. Now, in our previous work, we looked at not just the NFL players, but we looked at over 600, I think it was 636 or so people who played football across the entire range from one year of football all the way up to 30 years of football. And in that study, we found a very clear dose response relationship between both the duration of play and the cumulative force to the head that these individuals experienced, and both the likelihood of CTE and for those that got it, the severity of CTE.
So the best predictor that we have right now for whether or not someone's going to develop CTE, it appears to be the cumulative force to the head that someone experiences over their entire life. Of note, concussion did not predict CTE status. Of note, position played at the highest level did not predict CTE status. It really appears to be that cumulative force to the head.
Dr. Shuvro Roy:
It's those cumulative sub-concussive hits that seem to be the most predictive for the body of work that we've seen thus far. Now, in prior work in this space, as you just mentioned, there has seemingly not been a correlate between CTE and football position played. That was always surprising to me. You might think that positions, there is that repeated trauma, offensive line, defensive line, linebackers, running backs, et cetera, would seemingly be at higher risk. In this study, you had some newer findings. Could you take us through those findings related to position played and the implications there?
Dr. Daniel Daneshvar:
In this study and in previous work, we found that there isn't really a great link between position played at the highest level and CTE status. Now, of note, part of the issue is that we think of these repeated head impacts in terms of the number of hits, but what appears to matter more is the number times the force of those hits. And so folks like the linemen who are getting a lot of hits tend to be getting lower G-force hits. And in fact, actually, when you look at the cumulative force to the head, the relative difference between positions, they aren't that high. They exist, but they aren't that high. But it's actually the running backs who get the highest combination of force and number of hits versus the lineman. Now, another thing that we note is we think of these other hits that don't result in concussion.
We often refer to them as sub-concuss, and that terminology is actually problematic because it masks the fact that so many of these head impacts are actually really substantial. For example, based on helmet sensor data, for a given offensive lineman in college who gets a concussion, going back and looking at all of the head impacts that that person experienced, for every head impact that resulted in a concussion, on average, that offensive lineman experienced 41 hits to the head of equal or greater force than the head impact that resulted in that concussion. And for that reason, we don't think that the term sub-concussive is really the best name for those impacts that don't result in concussions because sub implies that it's less than, when in fact, very many of these head impacts are technically, if you had to give it a name, supra, they're greater than the force of a concussion.
And we published this in BJSM a couple years ago. We think the terminology should actually be non-concussive so that there are impacts that result in symptoms or signs, that's a concussive injury, but that there are impacts that don't result in signs or symptoms of concussion. Those are separate, those are non-concussive, and many of them can accumulate and cause subclinical traumatic brain injuries.
Dr. Shuvro Roy:
I have certainly been guilty of using the term sub-concussive, so I will be correcting my terminology as well, and that's quite helpful. One thing actually you mentioned with the running backs, while there was no difference in the rate of CT presence, was there any difference that we saw with the presence of stage four CTE by position?
 Dr. Daniel Daneshvar:
One of the issues when we're looking at NFL players is that most NFL players, they didn't stick with one position. Most players, if you are a wide receiver at the NFL, many of them were the best player in their high school and were pretty much playing every position, but most often quarterback because you wanted your best player in the position that had the most touches. And so that's one of the problems when we look at the highest levels of play. But when we did look at highest level of play, what we found is that individuals who had stage four CTE were actually most likely to be running backs and least likely to be defensive linemen. So these data lined up really well with our 2023 Nature Communications paper where we similarly found that it appeared that the running backs were the ones that got that highest cumulative G-force. These data support those.
Dr. Shuvro Roy:
That is really helpful context. And actually to your point of players over the course of their careers, when we look at this cohort, obviously a cohort of professional athletes that develop CTE, the burning question for those listening is how should we counsel younger players, youth, high school, college football players from these data? Is there anything new to counsel them on based on these results?
Dr. Daniel Daneshvar:
This was a study of NFL players, and so the data only explicitly applied to NFL players, but their cumulative head impact exposure didn't start at the pro level. They had exposure in college, in high school, and many at the youth level. And so all of those head impacts matter. The accumulation of all of those, that cumulative force is what increases one's risk of problems later in life. And so if the background prevalence of CTE is somewhere south of 1%, like 0.6, 0.8%, and the prevalence in NFL players was at an absolute minimum under the most conservative assumptions, 25%, that's disconcerting then for those lower levels of play. And so that's where we need to think about ways that we can be more intentional about that cumulative force to the head that athletes are experiencing. And what I mean by that is doing things that reduce that cumulative force.
Dr. Shuvro Roy:
I just am curious, do you feel like we have made progress in that way? When I interviewed Dr. McKee three years ago, for example, we didn't necessarily have these new Guardian caps that are placed over the helmet for practice, and now we even see them in games. Do you feel like we've made progress in that way?
Dr. Daniel Daneshvar:
People are very excited about equipment and technological changes and their ability to influence cumulative force to the head, but I'm not convinced. I haven't seen data that's particularly convincing. What I mean by that is the Guardian caps that are used at the professional level, first off, those are ones that are not available below the professional level. So those are different than the ones that are being sold at the college and high school level. But those Guardian caps in lab testing have been shown to attenuate the force associated with the impacts by something like 7%. And so you're taking on average a 27G impact and you're making that 27G impact on average about a 25G impact. Pretty substantial head impact still. Now, the Guardian caps that are available at below the professional level, in lab testing, those have been shown to attenuate the forces associated by linear impact by about 3%.
So you're taking on average a 27G impact and you're making it a 26 and change G impact. So I'm not particularly convinced that's going to be where the bulk of the difference is. Now, on the other hand, we know that nearly 70% of head impacts occur in practice. We also know that at the professional level, there's fewer than one contact practice per week. So if the college and high school and youth players practiced like the pros practice, we would eliminate more than half of the head impacts. We'd be making those 27G impacts, zero G impacts for up to 70% of them. That seems like it's a lot more bang for our buck, so to speak. And when you're talking about a few percent here or the majority there, a change that wouldn't affect a single minute of game time can get us a lot more power.
Dr. Shuvro Roy:
Those are eye-opening numbers. I was not aware, for example, that when we look at the guardian cap data, that it's only a 7% reduction. And to your point, the vast majority of contact being in practice does seem like a lower hanging fruit. Finally, I would like to close with this. This study has placed a spotlight on the prevalence of CTE being far more common amongst NFL players than previously thought. I think this is the first time we've done a neurology podcast where we actually saw a study published in an ESPN article before we've even seen it in the journal itself. Where do you hope we can go from here? What do we still need to learn about CTE?
Dr. Daniel Daneshvar:
Right now, CTE can only be diagnosed with known accuracy after someone passes away. And so we need to move from understanding CTE, which is critically important, to diagnosing and treating CTE, but we're making incredible strides on that front. We are identifying factors that help us diagnose the disease both based on clinical markers and objective markers, and we're also improving the ability to identify potential treatments for this disease. We should not get to the point where we can say an athlete has CTE in life and then not be able to provide that athlete with a treatment that meaningfully affects their risk of progression of disease. And so that's where we really need to be focused.
Dr. Shuvro Roy:
Dan, you've been generous with your time. Thank you so much. Again, the article is titled Prevalence of Chronic Traumatic Encephalopathy and Death in National Football League Players: A Retrospective Population-Based Cohort Study published in BMJ. That has been today's Neurology Podcast. Thanks for tuning in.
Dr. Daniel Daneshvar:
Real pleasure to be here. Thank you.
Dr. Stacey Clardy:
This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org/podcast for our full list of past episodes, or you can also search by keyword on your podcast app for any neurology-specific topics you want to learn about.

Dr. Kait Nevel talks with Dr. Katharina Schmidbauer about primary CNS T-cell lymphoma, highlighting diagnostic challenges, imaging characteristics, and treatment approaches for this rare disease. 
Read the related article in Neurology®. 
Disclosures can be found at Neurology.org. 
Podcast Transcript:
Dr. José Merino:
This is José Merino, editor-in-chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week.
 
Dr. Kait Nevel:
Hello, my name is Kait Nevel. Today, I am interviewing Katharina Schmidbauer on her article, "Clinical Manifestations of Primary CNS T-Cell Lymphoma." Welcome to the Neurology Podcast. And Katharina, I would love to hear a little bit about you.
Dr. Katharina Schmidbauer:
Thank you, Kait. Thank you for having me. It's a pleasure. I am a neurologist with a great research interest in neuro-oncology, working at the University Hospital of Munich.
Dr. Kait Nevel:
Wonderful. Thank you for that. What do you think the most important takeaway is from your article for the practicing neurologist?
Dr. Katharina Schmidbauer:
Primary CNS T-cell lymphoma is very rare and the diagnosis is often really difficult to establish. In this study, we present hallmarks of the disease that could help with the diagnosis in the future. And our case series really illustrates many diagnostic challenges. The first important message would be how to deal with diagnostic uncertainty. If you have a progressive tumefactive CNS lesion and the clinical course, the imaging, and pathology don't quite fit together, CNS lymphoma and also T-cell CNS lymphoma need to remain on the differential, even if the first biopsy is inconclusive. And in this context, it's also important to avoid, of course, steroids before biopsy because they could cause regression of the lesion and therefore make the biopsy non-diagnostic, which is not the same as a negative biopsy.
Dr. Kait Nevel:
Thank you for that. And before we get into some more of the details of the findings of your study, could you give us a brief overview of the background and methods of your study?
Dr. Katharina Schmidbauer:
Sure. Primary CNS T-cell lymphoma is very rare and an aggressive subtype of CNS lymphoma. Most primary CNS lymphomas are B-cell lymphomas, but for T-cell lymphoma, we have very little systematic data. In fact, there are only three case series so far, and therefore we performed a multicenter retrospective study across three centers in Munich, Heidelberg, and Boston. And there we identified 16 adult patients with histologically confirmed primary CNS T-cell lymphoma without systemic disease treated between 2008 and '24. We looked at several levels of the disease, the clinical presentation, of course, histopathology, immunophenotype, T-cell receptor gene rearrangement testing, and if available, next-generation sequencing. And we also gathered MRI and PET imaging, treatment regimes, and of course outcome data. We also centrally reviewed the imaging and histopathology results in a multidisciplinary setting. And the study is mainly of course descriptive. However, we also tried to find associations that are relevant for outcome.
Dr. Kait Nevel:
Getting into some of the things that you found or discovered through this study, what's one thing that surprised you?
Dr. Katharina Schmidbauer:
One surprising finding of the study was the heterogeneous presentation on MRI and the high number of misdiagnosis on MRI in more than half of the patients. If you look into the imaging figures in the paper, these tumors can present as like any other disease. They can mimic neuroinflammatory disease, high-grade glioma, small vessel disease, and even meningioma or leptomeningeal disease. So the most common misdiagnosis was high-grade glioma, and indeed these lesions often showed very infiltrative growth patterns and almost streaky or perivascular patterns of contrast enhancement. And another interesting finding was the PET imaging. You might expect an aggressive tumor to show very high metabolic activity on FET PET, such as in high-grade glioma. But in our small subgroup of patients who underwent FET PET imaging, uptake was often relatively low to moderate or also completely photopenic, especially on FDG PET.
Dr. Kait Nevel:
Yeah. I found that part of your findings fascinating that the imaging is so unlike what we see in the much more common diffuse large B-cell lymphoma that we see in the CNS. It's much more common than T-cell lymphoma. Was there any understanding of why the imaging looks so different, particularly on the PET and FET imaging, as you mentioned?
Dr. Katharina Schmidbauer:
CNS lymphoma is a very heterogeneous entity itself. And we also know that from other PET imaging studies and CNS lymphoma that it can present heterogeneously with low or moderate, but also high uptake. And on MRI, we also know that in the CNS lymphoma, it's not always the common picture and the involvement of subcortical or deep brain structures. So it's a mimicking disease also in other studies, but in this rare subtype of T-cell lymphoma, this was pretty striking. Yeah.
Dr. Kait Nevel:
One thing that you've already mentioned that stood out to me was the number of initial misdiagnoses before reaching a diagnosis of primary CNS T-cell lymphoma. How do we work as a team, do you think, when we're evaluating these patients to reach the correct diagnosis more quickly? Is there anything that we should be doing differently?
Dr. Katharina Schmidbauer:
I feel the solution is early multidisciplinary discussion. We need to involve all disciplines pretty early, neuroradiology, neuropathology, and neurosurgery of course, and plan the diagnostic steps together, especially the biopsy. In some cases, we also used FET PET imaging to look for potential hotspots within the lesion that might provide a more representative biopsy target. Interestingly, of course, the uptake was only moderate in our cases, but I would potentially give it a try to have additional information when to plan and where to plan the biopsy. Of course, also histopathology needs to be regarded when we talk about misdiagnosis. I don't have a good explanation for why even when we obtain enough tissue, some characteristic findings we would expect such as T-cell receptor clonality were simply not detected. Yeah, this is not solved so far.
Dr. Kait Nevel:
Has anything you discovered in your results changed the way that you evaluate patients with brain lesions that have yet to be diagnosed or maybe the patient who has an unusual imaging or unusual clinical history coupled with imaging that maybe isn't totally typical for anything?
Dr. Katharina Schmidbauer:
Yeah, there are several things. I would be cautious about the diagnostic approach and sometimes especially the imaging or also the histopathology creates some uncertainty. If CNS T-cell lymphoma or CNS lymphoma in general is suspected, I would try very hard to obtain tissue before the application of steroids. This is maybe the first point. And next is how I deal with an apparently negative biopsy. I would distinguish between a truly negative biopsy and a non-diagnostic biopsy. So the histopathology findings show non-specific inflammation. For example, I would ask, was the patient exposed to steroids? Was enough viable tissue obtained? Was the right part of the lesion sampled? Was there necrosis? And also what you mentioned, how is the imaging pattern and does it fit also the clinical course? Is it relevant like the lesion behaves? Is it like an inflammatory disease? Does it regress and recur or progressively enlarge?
If these questions leave you uncertain, then I would plan to reperform another biopsy. But what sometimes happens in the retrospective of the study, in some cases you jump to the next plausible diagnosis and of course, such as an inflammatory tumefactive CNS lesion that may also have responded to steroid treatment in the beginning, you could also go with another plausible diagnosis. So we need to be careful to reassure is it really a negative biopsy or is it a non-diagnostic one and how to proceed?
Dr. Kait Nevel:
What did you learn about outcomes in your patient cohort and do you think that we can use your results to guide treatment decisions for patients with primary CNS T-cell lymphoma?
Dr. Katharina Schmidbauer:
Yeah, of course we looked also at associations with outcome based on the treatment regimens that we found in our study. However, in my view, our results provide somehow supportive evidence, but I would be careful about using the small retrospective series to recommend specific treatment regimes. In our cohort, MTX-based treatment was commonly used and patients who received high-dose MTX-based treatment with autologous stem cell transplantation had longer overall survival, which is of course consistent with general treatment principles we know from primary CNS B-cell lymphoma. But of course we have only 16 patients and there is obviously substantial selection bias. Younger and fitter patients are more likely to receive intensive treatment and transplantation. So overall, I would say that our results support MTX-based treatment, including stem cell transplantation in selected patients as an important therapeutic strategy.
Dr. Kait Nevel:
Do you think that it is important or helpful to get next-generation sequencing on the samples of patients who have established primary CNS T-cell lymphoma?
Dr. Katharina Schmidbauer:
I would say molecular characterization is really important, but I would not say that every patient needs broad NGS. In my view, it's extremely valuable when you have an unusual histological phenotype, diagnostically difficult case, disease relapse, or when the result could potentially change treatment. And of course our ALK1-positive case is a good example. She had a fast progressive subtype and of course knowing about the mutation that changed the treatment algorithm, but in other cases we look at our small NGS subgroup. We also found variants of uncertain significance and we cannot term them as pathogenic mutations. So I would go for it if you have the facility to do it, but maybe not in every case.
Dr. Kait Nevel:
That makes sense. And it sounds like important to consider because as you highlight in our conversation and in your paper, you can uncover something that could be potentially pretty impactful to treatment for some patients. What do you think that we could do to learn more about this very rare oncologic condition? I mean, in your study, this was a multicenter. There were three different centers involved over a decade, almost 14-year timeframe, I think it was, or 16 years.
Dr. Katharina Schmidbauer:
Yeah, exactly.
Dr. Kait Nevel:
And you identified 16 patients, so about one patient per year over three academic centers, so pretty rare. What can we do or what do you think we should do as a neuro-oncologic community maybe to understand this group of heterogeneous, somewhat heterogeneous diseases better?
Dr. Katharina Schmidbauer:
The biggest challenge is of course the rarity of the disease and to gain any evidence that is useful. So as a single center, we would have never had enough patients and international collaboration of course is key for gaining any evidence. Yeah, I'm also really thankful for the great work and collaboration with the centers in Heidelberg and Boston. But yeah, we need larger registries for rare CNS tumors and ideally prospective standardized data sets to gather all the relevant information. And of course, I believe there are many distinct molecular subgroups of primary CNS lymphoma. They may behave differently or respond differently to treatment. And the next step in my view would be to really focus on the molecular subtypes and also aim for biology-driven treatment. But still the first steps, the number of misdiagnosed cases is maybe also not that low and should in the first place aim for not to miss any diagnosis of primary CNS T-cell lymphoma and to remember to keep it on the differential.
Dr. Kait Nevel:
Yeah, that sounds like a good goal. And your article and this podcast hopefully is a call out to people to remember this in the differential diagnosis for patients who have brain lesions, that it's not really clear what they are and diagnosis has been elusive to keep this in the list of possibilities.
Dr. Katharina Schmidbauer:
That would be great. Yeah.
Dr. Kait Nevel:
Great. Thank you so much for talking with me today, Katharina, and thank you for sharing more information about your study with us and educating all of us about primary CNS T-cell lymphoma.
Dr. Katharina Schmidbauer:
Thank you so much for having me.
Dr. Kait Nevel:
So again, I've been talking with Katharina Schmidbauer about her article, "Clinical Manifestations of Primary CNS T-Cell Lymphoma."
Dr. Stacey Clardy:
This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org/podcast for our full list of past episodes, or you can also search by keyword on your podcast app for any neurology-specific topics you want to learn about.